A new role for PGRP-S (Tag7) in immune defense: lymphocyte migration is induced by a chemoattractant complex of Tag7 with Mts1

PGRP-S (Tag7) is an innate immunity protein involved in the antimicrobial defense systems, both in insects and in mammals. We have previously shown that Tag7 specifically interacts with several proteins, including Hsp70 and the calcium binding protein S100A4 (Mts1), providing a number of novel cellular functions. Here we show that Tag7–Mts1 complex causes chemotactic migration of lymphocytes, with NK cells being a preferred target. Cells of either innate immunity (neutrophils and monocytes) or acquired immunity (CD4⁺ and CD8⁺ lymphocytes) can produce this complex, which confirms the close connection between components of the 2 branches of immune response.     

Assignment of heme resonances and determination of the electronic structures of high- and low-spin nitrophorin 2 by 1H and 13C NMR spectroscopy: an explanation of the order of heme methyl resonances in high-spin ferriheme proteins

The (1)H NMR resonances of the heme substituents of the low-spin Fe(III) form of nitrophorin 2, as its complexes with N-methylimidazole (NP2-NMeIm) and imidazole (NP2-ImH), have been assigned by a combination of (1)H homonuclear two-dimensional NMR techniques and (1)H-(13)C HMQC. Complete assignment of the proton and partial assignment of the (13)C resonances of the heme of these complexes has been achieved. Due to favorable rates of ligand exchange, it was also possible to assign part of the (1)H resonances of the high-spin heme via saturation transfer between high- and low-spin protein forms in a partially liganded NP2-NMeIm sample; additional resonances (vinyl and propionate) were assigned by NOESY techniques. The order of heme methyl resonances in the high-spin form of the protein over the temperature range of 10-37 degrees C is 8 = 5 > 1 > 3; the NMeIm complex has 5 > 1 > 3 > 8 as the order of heme methyl resonances at <30 degrees C, while above that temperature, the order is 5 > 3 > 1 > 8, due to crossover of the closely spaced 3- and 1-methyl resonances of the low-spin complex at higher temperatures. This crossover defines the nodal plane of the heme orbital used for spin delocalization as being oriented 162 +/- 2 degrees clockwise from the heme N(II)-Fe-N(IV) axis for the heme in the B orientation. For the NP2-ImH complex, the order of heme methyl resonances is 3 > 5 > 1 > 8, which defines the orientation of the nodal plane of the heme orbital used for spin delocalization as being oriented approximately 150-155 degrees clockwise from the heme N(II)-Fe-N(IV) axis. In both low-spin complexes, the results are most consistent with the exogenous planar ligand controlling the orientation of the nodal plane of the heme orbital. In the high-spin form of NP2, the proximal histidine plane is shown to be oriented 135 degrees clockwise from the heme N(II)-Fe-N(IV) axis, again for the B heme orientation. A correlation between the order of heme methyl resonances in the high-spin form of NP2 and several other ferriheme proteins and an apparent 90 degrees shift in the nodal plane of the orbital involved in spin delocalization from that expected on the basis of the orientation of the axial histidine imidazole nodal plane have been explained in terms of bonding interactions between Fe(III), the axial histidine imidazole nitrogen, and the porphyrin pi orbitals of the high-spin protein.     

FlowMax: A Computational Tool for Maximum Likelihood Deconvolution of CFSE Time Courses

The immune response is a concerted dynamic multi-cellular process. Upon infection, the dynamics of lymphocyte populations are an aggregate of molecular processes that determine the activation, division, and longevity of individual cells. The timing of these single-cell processes is remarkably widely distributed with some cells undergoing their third division while others undergo their first. High cell-to-cell variability and technical noise pose challenges for interpreting popular dye-dilution experiments objectively. It remains an unresolved challenge to avoid under- or over-interpretation of such data when phenotyping gene-targeted mouse models or patient samples. Here we develop and characterize a computational methodology to parameterize a cell population model in the context of noisy dye-dilution data. To enable objective interpretation of model fits, our method estimates fit sensitivity and redundancy by stochastically sampling the solution landscape, calculating parameter sensitivities, and clustering to determine the maximum-likelihood solution ranges. Our methodology accounts for both technical and biological variability by using a cell fluorescence model as an adaptor during population model fitting, resulting in improved fit accuracy without the need for ad hoc objective functions. We have incorporated our methodology into an integrated phenotyping tool, FlowMax, and used it to analyze B cells from two NFκB knockout mice with distinct phenotypes; we not only confirm previously published findings at a fraction of the expended effort and cost, but reveal a novel phenotype of nfkb1/p105/50 in limiting the proliferative capacity of B cells following B-cell receptor stimulation. In addition to complementing experimental work, FlowMax is suitable for high throughput analysis of dye dilution studies within clinical and pharmacological screens with objective and quantitative conclusions.     

The effect of axial ligand plane orientation on the contact and pseudocontact shifts of low-spin ferriheme proteins

 The effect of axial ligand nodal plane orientation on the contact and pseudocontact shifts of a symmetrical low-spin octamethylferriheme center has been calculated as a function of the angle of the axial ligand. Simple Hückel techniques have been used to estimate the contact contribution, and values obtained from model hemes, together with counter-rotation of the g-tensor, have been used to estimate the pseudocontact contribution, for the eight β-pyrrole methyl and four meso-H positions. It is found that the maximum and minimum contact shifts occur when the axial ligand is aligned at an angle of ±15° to the meso-H axes of the heme, rather than when the axial ligand plane lies along the porphyrin nitrogens, as assumed previously by some investigators. For systems having one planar axial ligand or two ligands in parallel planes, the contact and pseudocontact contributions at the meso-H positions are comparable in size (at least on the basis of simple Hückel estimates), while the contact contribution clearly dominates the isotropic shifts of the heme methyls. Allowing for the substituent effect of the 2,4-vinyls of protohemin, or the 2,4-thioethers of hemin c, as well as the average diamagnetic shifts of the heme methyls and meso-H, plots of the predicted shifts as a function of axial ligand nodal plane orientation have been constructed for hemin b- and c-containing proteins. Excellent agreement in the order of shifts, and reasonable agreement in the sizes of the observed shifts, is observed in the majority of the ferriheme proteins for which the methyl and meso-H resonances have been assigned and proton shifts reported. Plots have also been constructed for hemin c-containing proteins having the two axial ligand nodal planes oriented at relative angles of 40°, 70°, and 80°. Excellent agreement in the order of shifts, and reasonable agreement in the magnitudes of the observed shifts, is observed in all cases of bacterial cytochromes which do not fit the plots that assume the ligands are in parallel planes, except one – the cytochrome c-552 of Nitrosomonas europae. Except for this case, where the order of the predicted methyl shifts at any angle of the axial ligands disagrees with the observed, the reasons can usually be attributed to a large dihedral angle between two axial ligand nodal planes, to strong H-bonding interactions involving His and/or CN^– ligands, or to off-axis binding of one (or both) axial ligand(s). Ruffling of the porphyrin ring may also contribute to the contact shift in as yet undefined ways. Hence, despite the simplicity of the calculations, the agreement with observed data is highly satisfying and the concept of the importance of axial ligand plane orientation on the observed proton shifts of heme proteins is fully confirmed. Received: 15 June 1998 / Accepted: 6 August 1998     

The influence of cortical feature maps on the encoding of the orientation of a short line

The inhomogeneous distribution of the receptive fields of cortical neurons influences the cortical representation of the orientation of short lines seen in visual images. We construct a model of the response of populations of neurons in the human primary visual cortex by combining realistic response properties of individual neurons and cortical maps of orientation and location preferences. The encoding error, which characterizes the difference between the parameters of a visual stimulus and their cortical representation, is calculated using Fisher information as the square root of the variance of a statistically efficient estimator. The error of encoding orientation varies considerably with the location and orientation of the short line stimulus as modulated by the underlying orientation preference map. The average encoding error depends only weakly on the structure of the orientation preference map and is much smaller than the human error of estimating orientation measured psychophysically. From this comparison we conclude that the actual mechanism of orientation perception does not make efficient use of all the information available in the neuronal responses and that it is the decoding of visual information from neuronal responses that limits psychophysical performance. Action Editor: Terrence Sejnowski     

Human age reversal: Fact or fiction?

Although chronological age correlates with various age‐related diseases and conditions, it does not adequately reflect an individual''s functional capacity, well‐being, or mortality risk. In contrast, biological age provides information about overall health and indicates how rapidly or slowly a person is aging. Estimates of biological age are thought to be provided by aging clocks, which are computational models (e.g., elastic net) that use a set of inputs (e.g., DNA methylation sites) to make a prediction. In the past decade, aging clock studies have shown that several age‐related diseases, social variables, and mental health conditions associate with an increase in predicted biological age relative to chronological age. This phenomenon of age acceleration is linked to a higher risk of premature mortality. More recent research has demonstrated that predicted biological age is sensitive to specific interventions. Human trials have reported that caloric restriction, a plant‐based diet, lifestyle changes involving exercise, a drug regime including metformin, and vitamin D3 supplementation are all capable of slowing down or reversing an aging clock. Non‐interventional studies have connected high‐quality sleep, physical activity, a healthy diet, and other factors to age deceleration. Specific molecules have been associated with the reduction or reversal of predicted biological age, such as the antihypertensive drug doxazosin or the metabolite alpha‐ketoglutarate. Although rigorous clinical trials are needed to validate these initial findings, existing data suggest that aging clocks are malleable in humans. Additional research is warranted to better understand these computational models and the clinical significance of lowering or reversing their outputs.     

AmylPepPred: Amyloidogenic Peptide Prediction tool

We present an efficient computational architecture designed using supervised machine learning model to predict amyloid fibril forming protein segments, named AmylPepPred. The proposed prediction model is based on bio-physio-chemical properties of primary sequences and auto-correlation function of their amino acid indices. AmylPepPred provides a user friendly web interface for the researchers to easily observe the fibril forming and non-fibril forming hexmers in a given protein sequence. We expect that this stratagem will be highly encouraging in discovering fibril forming regions in proteins thereby benefit in finding therapeutic agents that specifically aim these sequences for the inhibition and cure of amyloid illnesses.

Availability

AmylPepPred is available freely for academic use at www.zoommicro.in/amylpeppred